Allergic rhinitis affects 20% of the adult population and up to 40% of children. Although rhinitis itself is not life threatening (unless accompanied by severe asthma or anaphylaxis), morbidity from the condition can be significant. Allergic rhinitis often coexists with other disorders, such as asthma, sinusitis, nasal polyps, allergic conjunctivitis, and atopic dermatitis. Rhinitis may also considerably reduce quality of life, productivity, learning, etc. Furthermore, insufficient therapy of rhinitis may lead to other disorders including infection of the sinuses, ears and lower respiratory tract. Effective therapy for allergic rhinitis requires understanding the pathophysiology of the disease, as well as the role of various inflammatory mechanisms. As such, various classes of medication are at the physicians' disposal to treat patients with allergic rhinitis. Among these are 2nd generation antihistamines and anticholinergic agents, intranasal corticosteroids, and mast cell stabilizers. Recently, leukotriene (LT) receptor antagonists have been added to the modes of therapy.
The mechanism of allergic rhinitis is a typical allergic disease. With regard to its pathophysiology, there are several similarities between rhinitis and asthma. Rhinitis is defined as inflammation of the nasal membranes and is characterized by a symptom complex that consists of any combination of the following: sneezing, nasal congestion, nasal itching, and rhinorrhea. To date, histamine H1-receptor antagonists, decongestants, sodium cromoglycate, corticosteroids, cysLT-receptor antagonists and anticholinergics are most commonly used pharmacological agents for the treatment of rhinitis.
Asthma bronchiale, affecting as many as 10% of individuals in industrialized nations, is characterized by bronchoconstriction, chronic airway inflammation, airway hyperreactivity, and mucosal oedema. Airway remodelling and altered non-cholinergic, nonadrenergic neurotransmission may contribute to irreversible airway obstruction and reduction of pulmonary function. Asthma bronchiale has emerged as a major public health problem worldwide over the past 20 years. Although data indicate that current asthma therapies led to limited decreases in death rates, it continues to be a significant health care problem. It still is one of the leading causes of preventable hospitalization worldwide and accounts for several million lost workdays. Along with the increase in asthma prevalence, the costs associated with this disease have also risen dramatically.
The pathophysiology of asthma involves an intricate network of molecular and cellular interactions, although the contribution of each individual factor is probably different from patient to patient depending on the setting and stimulus. Major participants in the development of an asthma phenotype include the triggering stimuli such as the allergens themselves, cells such as T cells, epithelial cells and mast cells that produce a variety of cytokines including IL-5, GM-CSF, IL-3, IL-4 and IL-13 and chemokines such as eotaxin, adhesion molecules, etc. Recent advances in understanding the inflammatory and immunological mechanisms of asthma have indicated many potential therapeutic avenues that may prevent or reverse abnormalities that underlie asthma.
At present, pharmacotherapy is the mainstay of treatment of asthma. Short- and long-acting inhaled β2-adrenoceptor agonists are available. The short-acting β2-adrenoceptor agonists are now used on an on-demand-basis for rapid relief of symptoms. In recent years, long-acting inhaled β2-adrenoceptor agonists have had an increasing role in the management of asthma, particularly in patients with moderate to severe asthma. Antimuscarinic drugs are rather less efficacious in the relief of an asthma attack than the β2-adrenoceptor agonists (Rodrigo and Rodrigo, Chest 2002; 121:1977-87). However, with the introduction of the new anticholinergic tiotropium, the use of anticholinergics in respiratory diseases will enormously increase. Inhaled corticosteroids have become the mainstay of therapy in chronic asthma. They are the most clinically effective treatment available but can produce serious secondary effects and, moreover, be inefficient in corticosteroid-resistant asthmatics.
Chronic obstructive pulmonary disease (COPD) is also very common. This disease is characterized by a progressive airflow limitation accompanied by inflammatory reactions. From a review of data from all over the world, it is clear that tobacco is not the only cause of COPD. The worldwide increasing age is also a certain risk factor. The prevalence of COPD varies between 3% and 10% with a steadily increasing trend. Although COPD is a leading cause of illness and death, its recognition as a public health problem has been slow to evolve despite the rising mortality rate for COPD and the decline in death rates for most of the cardiovascular diseases (Hurd Chest 2000; 117(2 Suppl):1S-4S). Additionally, COPD imparts substantial economic burden to individuals and society.
In general, much less is known about the pathogenesis of COPD than that of asthma. Recent studies have greatly expanded the understanding of pathogenetic mechanisms underlying COPD. Thus, there is consent that COPD is also an inflammatory disease. From the present pathogenetical point of view, neutrophil granulocytes, CD8+ lymphocytes and macrophages with their mediators probably play crucial roles in the pathogenesis of COPD.
The current management is focussed on the improvement of the lung function of patients suffering from COPD. The first step is in this process smoking cessation. There is evidence that smoking reduction or cessation may result in improvement of some respiratory parameters. Bronchodilators (β2-adrenoceptor agonists and anticholinergics) are now the mainstay of symptomatic therapy. Short- and long-acting β2-adrenoceptor agonists such as salbutamol, fenoterol, salmeterol, formoterol are established therapeutics in the symptomatic COPD management. Of the short-acting antimuscarinic drugs, ipratropium is widely used. Recently, tiotropium, a long-acting anticholinergic with a certain preference to M3-muscarinic receptors has now been introduced world-wide (Hansel and Barnes, Drugs Today (Barc) 2002; 38:585-600). Anticholinergic agents can effectively be used in the treatment of COPD in horses, as well. Ipratropium at a dose of 2,400 μg/horse is an effective bronchodilator in horses with COPD (Duvivier et al. Equine Vet J 1999; 31:20-4, Bayly et al. Equine Vet J. 2002 Jan; 34(1):36-43). At present, the anti-inflammatory therapy of COPD is unsolved. The use of systemic and inhaled glucocorticoids for COPD has increased appreciably over the past 20 years. They have been tested on the premise that interference with inflammation in COPD should alter the course of the disease. Although inhaled corticosteroids have a proven benefit in the management of asthma, but until recently, their efficacy in non-asthmatic, smoking-related COPD was not evidence-based (Bonay et al. Drug Saf 2002; 25:57-71). Inhaled corticosteroids have relatively little impact on the inflammatory processes that characterize COPD (Adcock and Chung, Curr Opin Investig Drugs 2002; 3:58-60).
Airflow obstruction and airway inflammation are features of allergic rhinitis/asthma as well as COPD. There is strong evidence that airway inflammation is a predominant underlying problem in patients with rhinitis, asthma and COPD. Although the airway inflammation in rhinitis/asthma and COPD, respectively, involve different cell types, both diseases are of chronic inflammatory nature associated with cellular infiltration and activation. While allergic rhinitis and bronchial asthma is predominantly characterized by eosinophils and CD4 lymphocytes, neutrophil granulocytes, CD8 lymphocytes and macrophages appear to play a major role in the pathogenesis of COPD.
Asthma- and COPD-like diseases, respectively, can also occur in animals, e.g. in horses. There is evidence that LTB4 and LTD4 could contribute to the pathogenesis of equine COPD (Marr et al. Res Vet Sci 1998; 64:219-24). In horses, there is apparently a link between LTs generation and the cholinergic system. Neutrophilic inflammation in the airways and bronchospasm mediated via muscarinic receptors are features of COPD in horses. LTs are reported to be involved in the exacerbation of COPD. Indeed, mediators such as LTs augment the cholinergic response in equine airways (Olszewski et al. Am J Physiol 1999; 276:L522-9). There is also evidence that cholinergic activation (acetylcholine) stimulates alveolar macrophages to release lipoxygenase-derived products (LTB4 and CysLTs) (Sato et al. Am J Physiol 1998; 274:L970-9).
Rhinoviruses are the cause of more than 50% of respiratory tract infections. Complications of rhinovirus infections (e.g. common cold), which include for example the manifestation or exacerbations of asthma, can be significant in certain populations. Therefore, it may be of great advantage to minimize the potential adverse consequences by using an adequate therapy. Recently it has been demonstrated that rhinovirus colds induce bronchial inflammation with markedly enhanced expression of 5-LO pathway proteins (Seymour et al J Infect Dis 2002; 185:5404) indicating that the production of LTs in these airway is augmented. Consequently, LT antagonists appear to be able to reduce lung symptoms subsequent to virus infection (Bisgaard et al. Am J Respir Crit Care Med 2003; 167:379-83). Furthermore, it is well known that anticholinergics like ipratropium provide specific relief of rhinorrhea and sneezing associated with common colds (Hayden et al. Ann Intern Med 1996; 125:89-97).
Leukotrienes (LTs) are important mediators of the pathophysiology of allergic airway diseases such as asthma and rhinitis, and they are also involved in COPD. The main effects mediated via LTS are bronchoconstriction, airway inflammation, oedema and mucus hypersecretion.
Arachidonic acid metabolism via 5-lipoxygenase results in a group of biologically active lipids known as leukotrienes (LTs). LTB4 is a potent activator of leukocyte chemotaxis. Cysteinyl LTs (LTC4, LTD4, LTE4) account for the spasmogenic activity previously described as slow-reacting substance of anaphylaxis (SRS-A). These inflammatory mediators are produced by a number of cell types including mast cells, neutrophils, eosinophils, basophils, macrophages and monocytes. They exert their biological effects by binding and activating specific receptors (LTB4 at the BLT receptor, cysteinyl-LTs at the cysLT1-receptor). This occurs in a series of events that lead to contraction of the human airway smooth muscle, chemotaxis and increased vascular permeability, mucus hypersecretion, decrease of ciliary motility. These effects have led to their important role in the diseases of asthma, allergic rhinitis and COPD.
CysLT-receptor antagonists (e.g. zafirlukast, montelukast, pranlukast) derivatives of other LT-receptor antagonists, such as L-648,051, MK-571, verlukast (MK-0679), pobilukast (SK&F 104353), AS-35, ICI 204,219, etc.) represent an effective and well-tolerated treatment for asthma and allergic rhinitis in adults and children, particularly for exercise- and aspirin-induced asthma. They can also have clinical applications in the COPD. Recently, it has been suggested that zafirlukast, a cysLT-receptor antagonist may increase the tidal volume and alveolar ventilation in patients suffering from COPD (Bu et al. Chin Med J 2003; 116(3):459-461).
Even if there are no compelling clinical data for an additional contribution by LTB4 in human asthma, in other respiratory conditions such as COPD, which are characterised by pronounced neutrophil infiltration, it may be that the chemotactic properties of LTB4 are more important (Daniel and O'Byrne, Am Rev Respir Dis 1991; 143:S3-5). In patients suffering from COPD, the enhanced oxidative stress is paralleled by the increased ability of neutrophils to synthesize the chemotactic factor LTB4, and may ultimately contribute to the infiltration/activation of neutrophils into the airways of COPD patients (Santus et al. Am J Respir Crit Care Med 2004; [Epub ahead of print]). Additionally, there is a selective increase in exhaled LTB4 in patients with COPD (Montuschi et al. Thorax 2003; 58:585-8).
Anticholinergic medications have been accepted as an important treatment modality in diseases of the upper and lower airways, rhinitis, asthma and COPD. The muscarinic receptor antagonist, used in this invention will be a long-acting compound. Any compound of this type can be used in this combination therapy approach.
Glycopyrrolate, another quaternary ammonium anticholinergic compound, consists of four stereoisomers. Glycopyrrolate belongs to the so-called anticholinergic drugs and antagonizes the neurotransmitter acetylcholine at its receptor site. This effect leads to a considerable bronchodilatation and a reduced mucus secretion. It is poorly absorbed from mucus membranes, thus reducing anticholinergic side effects (Ali-Melkkila et al. Acta Anaesthesiol Scand 1993; 37:63342). Glycopyrrolate possesses no selectivity in As binding to the M1-M3 receptors. Kinetics studies, however, showed that glycopyrrolate dissociates slowly from M3 muscarinic receptors (Haddad et al. Br J Pharmacol 1999; 127:413-20). Similarly to tiotropium, this behavior explains glycopyrrolate's relative receptor selectivity and its long duration of action. Indeed, there is evidence that racemic glycopyrrolate produces considerable and long-lasting bronchodilatory effects both in asthmatic and in COPD patients (Walker et al. Chest 1987; 91:49-51, Schroeckenstein et al. J Allergy Clin Immunol 1988I; 82:115-9, Gilman et al. Chest 1990; 98:1095-8, Cydulka and Emerman, Ann Emerg Med 1995; 25:470-3). Additionally, the use of a topical anticholinergic medication (e.g. ipratropium or glycopyrrolate) in allergic rhinitis is both safe and effective in reducing the symptoms (Milford et al. J Laryngol Otol 1990; 104:123-5, Meltzer J Allergy Clin Immunol 1992; 90:1055-64). As rhinitis, asthma and COPD are characterized by increased mucus secretions, the antisecretory effect of anticholinergics such as glycopyrrolate is an additional advantage for their use in the therapy of these diseases.